Some pathogens infect cells and populate the cells during one or more phases of their (i.e., the pathogen's) life cycle, which may include at lease one replicating phase. These pathogens, also called intracellular pathogens, may or may not be parasitic to the host cell. Sometimes a change in the intracellular environment of the host cell, for example host cell nutrient or energy depletion, may cause the pathogen or a portion of the population of the pathogen to undergo a morphological change from a replicating phase into a non-replicating, persistent phase, also known as the cryptic phase.
While the pathogen is in the persistent phase, the infected cell or organ may not exhibit any signs or symptoms of the infection. The pathogen may remain in the persistent phase for an indeterminate period of time, until the intracellular environment becomes favorable for pathogen replication again. At such time, the pathogen may revert to an antimicrobial-susceptible, replicating phase, and the organism may exhibit signs and symptoms of infection. The infection may also spread from one cell or organ to another cell or a cell of another organism.
Persistent phases of pathogens may generally be resistant to antimicrobial agents, while replication phases may generally be susceptible to antimicrobial agents. Thus, in order to effectively treat an infected cell or organism with an antimicrobial agent, it is necessary to cause the pathogen to transform from a persistent phase to a replicating phase.
One example of an infectious intracellular pathogen having a life cycle that includes both persistent and replicating phases is Chlamydia pneumoniae (hereafter “C. pneumoniae”).
One known method for the detection and treatment of C. pneumoniae infections is described in U.S. Pat. No. 6,884,784 to Mitchell et al., filed Mar. 19, 2002, which is incorporated by reference herein. A disadvantage of the treatment disclosed therein is that it fails to adequately eliminate all of the cryptic phase of the infection in cells. Instead the method is focused on the administration of a combination of antimicrobial agents, over an extensive period of time, each directed toward a different phase of the Chlamydia life cycle.
The Chlamydiae family, of which C. pneumoniae are a member, are obligate intracellular prokaryotic microorganisms which parasitize eukaryotic cells and are ubiquitous throughout the animal kingdom. Members of the Chlamydia genus are considered bacteria with a unique multiphasic developmental cycle having distinct morphological and functional forms. This persistent developmental growth cycle alternates between 1) intracellular life forms, of which two are currently recognized, a metabolically-active, replicating organism known as the reticulate body (“RB”) and a non-replicating organism known as the cryptic phase; and 2) an extracellular life form that is an infectious, metabolically-inactive form known as the elementary body (“EB”). Chlamydial EBs may be either intracellular or extracellular, while the replicating phase and cryptic phase are always intracellular.
EBs are small (300-400 nm) infectious, spore-like forms which are metabolically inactive, non-replicating, and found most often in the extracellular environment. EBs are resistant to a variety of physical insults such as enzyme degradation, sonication and osmotic pressure. This physical stability is believed to be a result of extensive disulfide cross-linking of the cysteine-rich major outer membrane protein (“MOMP”).
When exposed to the oxidizing conditions in the extracellular environment of the host, the outer membrane of the EB is relatively impermeable, as well as resistant to inactivation. The EB is thus well suited to survive long enough outside of the host to be transmitted to a new host.
Infection by members of the genus Chlamydia may induce a significant inflammatory response at the cellular level. Despite this, clinically, the initial infection may vary frequently in the symptoms displayed, and may even be asymptomatic. Once fully established, Chlamydia species are difficult to eradicate, with frequent relapse following antibiotic therapy. Evidence also indicates that the Chlamydia may become dormant and may be shed in quantities too miniscule to reliably detect by culture.
C. pneumoniae is believed to cause, or contribute to, many chronic illnesses in mammals, and in particular humans. The current therapy for suspected/confirmed C. pneumoniae infection is with a short course (e.g., 2-3 weeks) of a single antibiotic. C. pneumoniae is susceptible in vitro to tetracycline, erythromycin, clarithromycin, and fluoroquinolones such as ofloxacin, levofloxacin, and sparfloxacin. Despite having this in vitro susceptibility, patients having C. pneumoniae infections may relapse following antibiotic therapy with these agents.
In vitro studies on the persistence of Chlamydia species, despite specific and appropriate antibiotic therapy, have suggested that the presence of antibiotics may promote the formation of a persistent intracellular, non-replicative state, typically referred to as the latent, persistent, or cryptic phase. This transformation can be thought of as a stringent response and may also be observed with nutrient starvation and exposure to γ-interferon. Thus, in this manner, the organism can escape antibiotic therapy as currently used in clinical practice.
In view of the chronic and persistent nature of Chlamydia infections, as well as the highly infective nature of Chlamydia EBs and their ability to reinfect cells, there is a need for antichlamydial therapy which totally or substantially eradicates the pathogen or population of pathogens from infected cells and/or organisms.
However, current medical practice does not provide any method suitable for the elimination of substantially all of a population of Chlamydia from an infected patient. Currently no method or composition is known that is able to eradicate the entire, or substantially entire, population of the pathogen in the cells. The failure of current treatments to accomplish such eradication is believed to be due to the resistance of the persistent phase to antimicrobial agents.
Accordingly, there is a need for more effective compositions and methods useful in the treatment of chronic intracellular infections, for example C. pneumoniae infections, which preferably do not cause undesirable side effects, yet are able to substantially eliminate the population of infectious agent from the organism.